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Synthesis of 4-Aminoquinazolines by Palladium-Catalyzed Intramolecular Imidoylation of N-(2-Bromoaryl)amidines

Authors

  • Dr. Gitte Van Baelen,

    1. Department of Chemistry & Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines & Systems, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands), Fax: (+31) 20-5987488
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  • Sander Kuijer,

    1. Department of Chemistry & Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines & Systems, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands), Fax: (+31) 20-5987488
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  • Lukáš Rýček,

    1. Department of Chemistry & Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines & Systems, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands), Fax: (+31) 20-5987488
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  • Dr. Sergey Sergeyev,

    1. Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp (Belgium), Fax: (+32) 32653233
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  • Elwin Janssen,

    1. Department of Chemistry & Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines & Systems, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands), Fax: (+31) 20-5987488
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  • Dr. Frans J. J. de Kanter,

    1. Department of Chemistry & Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines & Systems, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands), Fax: (+31) 20-5987488
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  • Prof. Dr. Bert U. W. Maes,

    Corresponding author
    1. Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp (Belgium), Fax: (+32) 32653233
    • Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp (Belgium), Fax: (+32) 32653233
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  • Dr. Eelco Ruijter,

    Corresponding author
    1. Department of Chemistry & Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines & Systems, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands), Fax: (+31) 20-5987488
    • Department of Chemistry & Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines & Systems, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands), Fax: (+31) 20-5987488
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  • Prof. Dr. Romano V. A. Orru

    Corresponding author
    1. Department of Chemistry & Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines & Systems, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands), Fax: (+31) 20-5987488
    • Department of Chemistry & Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines & Systems, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands), Fax: (+31) 20-5987488
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Abstract

Compared with the widespread use of carbonylative Pd-catalyzed cross-coupling reactions, similar reactions involving isocyanide insertion are almost virgin territory. We investigated the intramolecular imidoylative cross-coupling of N-(2-bromoaryl)amidines, leading to 4-aminoquinazolines. After thorough optimization of the reaction with respect to palladium source and loading, ligand, base, temperature, and solvent, a small library of 4-aminoquinazolines was prepared to determine the scope of this method. Various substituents are tolerated on the amidine and the isocyanide, providing efficient access to a broad range of diversely substituted 4-aminoquinazolines of significant pharmaceutical interest.

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